The myeloma “cure” trials CESAR and ASCENT, which are part of the IMF’s Black Swan Research Initiative® (BSRI) project, are active and ongoing, and I will be providing an update very soon. However, another aspect of the Black Swan project is to understand what causes myeloma and to develop prevention strategies. This is a key element of the iSttopMM study, in which full details of patients’ medical history, exposures, and DNA sequence information can be reviewed and assessed. But what questions do we ask? And what clues do we have to guide the discovery process?
Role of toxic chemicals
The health impact of toxic chemical exposure has been much in the news lately. Agricultural chemicals, such as pesticides and insecticides, have long been suspected in the causation of myeloma, and I have written about the data supporting the role of Agent Orange (contaminated with dioxins) in the health of Vietnam veterans. Unfortunately, there is disappointing news that the Senate Committee on Veteran Affairs is now not supporting implementation of the “Blue Water Navy Veterans Act 2017,” designed to compensate veterans exposed to Agent Orange who served within territorial waters of Vietnam but not on land. A National Center for Biotechnology Information (NCBI) report strongly supported the connection to myeloma, but was apparently set aside.
In a recent landmark legal case, a man who developed lymphoma as a result of agricultural exposure to Roundup weed killer won a $289 million settlement against Monsanto, the manufacturer of Roundup. This case has heated up the battle over whether glyphosate in Roundup causes cancer, including myeloma. Monsanto faces more than 5,000 similar lawsuits across the U.S.
Simultaneously, the EPA has now moved to curb the role of human health studies in the assessment of regulations for toxic chemicals, including glyphosate, atrazine, and chlorpyrifos, for which very strong evidence of toxicity is available. In a bizarre turn of events, these kinds of key patient health studies and the data emerging from them are being referred to as “secret science” in an effort to diminish their credibility.
This tactic is truly reminiscent of the “tobacco wars,” an era when the industry maintained that its products were perfectly safe, it was the science that was flawed. However, the link between cigarette smoking and lung cancer was actually known securely for over 50 years before regulations were put in place and the impact of even secondhand smoke acknowledged. The impact of such chronic, lower-dose exposure to toxins is central to understanding what may cause myeloma.
Exposures in daily life
Myeloma patients often say that they did not go to Vietnam, were not in New York City on 9/11, and never worked in a chemical factory. So how did they get myeloma? Without starting to terrify everyone, it is important to realize that there are many, many toxic chemicals in our daily lives, and some people can be especially susceptible to their effects.
For example, another story in the news describes a study of the food preservative sodium benzoate, a widely used chemical. The study shows that even at very low (“physiologic”) levels, benzoate changes DNA/chromosome function. Key genes linked to steroids, fats, and insulin can be affected. The benzoate is actually broken down to produce benzene, a known cancer-causing agent. Benzene is known to cause myeloma and has no lower level as a safe cutoff because it causes chromosome/DNA changes even at very low levels.
Multiple studies provide “proof of principle” that toxic chemicals are involved in causing myeloma. I wrote about these studies, which identify how cancer-causing chemicals disturb the immune system, and named many chemicals to avoid in a recent blog post.
A list of suspect chemicals
What we need to do now is to establish a list of the likely toxins and sources of exposure that directly link to myeloma. The list can be used both to inform people and to interrogate the data from Iceland and elsewhere. It will be possible to assess the strength of connections to both genetic and environmental factors. An additional factor to be considered is that chemicals transfer across the placenta to an unborn child. There are already concerns about the children of Vietnam veterans. A recent study links prenatal exposure to DDT (dichlorodiphenyltrichloroethane, an agricultural insecticide linked to myeloma) to the development of autism.
I was recently asked if being born prematurely is a risk factor for myeloma. I learned that three myeloma patients indicated they were premature and, perhaps, had compromised immune systems as a result. This is a completely new notion that has never been investigated—but certainly can be. We have much to learn.
New technologies to the rescue
It is now possible to use many new technologies to explore the beginnings and evolution of MGUS (monoclonal gammopathy of unknown significance), SMM (smoldering multiple myeloma), and active myeloma. Mass spectrometry— the new and very sensitive method for detecting and measuring the myeloma M-component in the blood and urine—will allow us to track back to the earliest trigger factor for the MGUS. It seems that this moment may be at a much younger age than previously anticipated, even below the age of 40 years. Identifying that moment provides an opportunity to study that early process.
The working hypothesis is that an infection or an immune reaction of some sort is probably the trigger factor at the onset of MGUS leading to myeloma. The problem is that a clone damaged by chemical injury is triggered, and in the setting of a weakened immune system, that clone can have the chance to expand and grow. These are the interactions we need to sort out.
Expectations for the future
Within the next three to five years, we will know how successful cure-trial therapy is. We will also know much more about the very earliest stages of multiple myeloma as a basis to develop true prevention strategies. Exciting times, indeed!
Dr. Brian G.M. Durie serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.